Nefazodone (SERZONE.RTM.), 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]-propyl-]5-ethyl-2,4-dihydro-4-(2-p henoxy-ethyl)-3H-1,2,4-triazol-3-one hydrochloride is a novel antidepressant chemically unrelated to tricyclic or tetracyclic antidepressants and the selective serotonin uptake inhibitors in current use. Its activity appears to be linked to the potentiation of serotonergic activity in vivo as it blocks serotonin 5-HT.sub.2 receptors and reversibly inhibits serotonin re-uptake. It does not inhibit monoamine oxidase and exhibits decreased anticholinergic, antihistamine, alpha-adrenergic and sedative activity relative to tricyclic antidepressants.
Currently nefazodone hydrochloride is available in the form of immediate-release tablets, which have to be dosed twice daily. Multiple (two or more) step titration to an effective dose is often needed to allow administration of a clinically effective dose while allowing development of tolerance to the serotonergic effects of the drug that some patients find uncomfortable during the initiation of treatment with nefazodone. A once daily formulation that (relative to equivalent doses of the immediate-release formulation) reduced or "blunted" plasma peak levels but still provided for appropriate exposure to the drug (similar area under the plasma drug concentration-time curve compared to equivalent doses of the drug given twice a day as the currently available immediate-release formulation) is very desirable.
There are several difficulties associated with the formulation of a nefazodone product for oral administration that allows the reliable prolonged delivery of drug required to permit once daily dosing. These are:
drug metabolism
drug solubility
total daily dose
Drug metabolism
Nefazodone exhibits a significant first-pass metabolism, with the result that the immediate-release tablets show a bioavailability of approximately 20% and significant levels of three pharmacologically-active metabolites, a triazoledione, hydroxynefazodone and m-chlorophenylpiperazine (mCPP). (1,2) It is often the case that extended-release of drugs subject to a first pass metabolism results in an increase in the extent of metabolism. Highly metabolized drugs are thus often considered inappropriate candidates for formulation as extended-release systems (3).
It has been suggested that the metabolite mCPP may be responsible for some of the undesirable effects associated with nefazodone administration. Nefazodone is in fact generally regarded as a well-tolerated drug when given in clinically effective doses of up to 450 mg three times a day. The metabolite mCPP is a partial agonist at the 5-HT.sub.2B and 5-HT.sub.2C receptors and has some activity, usually seen as antagonist activity, at 5-HT.sub.2A receptors (4,5,6,7). In rodents it has anxiogenic-like properties, causes hypoactivity, hypophagia, oral dyskinesia, penile erection and hyperthermia (8,9). A dose-dependent hypoglycemic effect of mCPP mediated through 5-HT.sub.2C or 5HT.sub.2B receptors is seen in rats (10). It has been shown to increase anxiety in humans (and can cause panic attacks), may precipitate migraine attacks in those susceptible to such attacks, can disrupt sleep, be hypophagic in humans also and may have psychotogenic effects (9). As many of these effects are antagonistic to the beneficial effects of nefazodone, and because some of the described effects of mCPP are reminiscent of some of the adverse effects of nefazodone, an objective of this invention would be to sustain release of the drug substance without increasing the amount of this metabolite produced relative to that seen with the immediate-release formulation following oral administration of the drug.
Nefazodone exhibits non-linear kinetics, with the observed increase in nefazodone plasma concentrations being greater than would be expected if they were proportional to the increase in dose (11). Nefazodone is metabolized by and also inhibits cytochrome P450 (CPY) 3A4. This isozyme is also responsible for the further metabolism of the triazoledione and hydroxynefazodone. Nefazodone is also a weak inhibitor of CYP2D6, which is responsible for the metabolism of mCPP (12). Because nefazodone can inhibit its own metabolism (and that of its metabolites) and because the metabolism can be saturated, non-linear pharmacokinetics of the drug result. This manifests itself as significant inter- and intra-individual variation in standard drug pharmacokinetic parameters such as AUC and Cmax, meaning that titration of the drug dose is required to maximize efficacy while minimizing undesirable effects.
We have found that by preparing a formulation that provides for careful control of the absorption rate of nefazodone from an orally administered dose form, it is possible to avoid significant loss of bioavailability of the drug. This is contrary to typical expectation for the administration of a highly metabolized drug in an extended-release formulation. Also in a distinction from prior art for formulating extended-release dosage forms of arylpiperazine psychotropic agents as exemplified by buspirone in U.S. Pat. No. 5,431,922, no significant increase in bioavailability is seen either. This is advantageous, permitting one to avoid adjusting the dose when transferring from immediate-release to extended-release nefazodone formulations of the current invention. Control of absorption rate by means of the novel formulation also results surprisingly in a reduction of the metabolite mCPP, which may result in reduced frequency and intensity of undesirable effects following oral administration of nefazodone.
Drug Solubility
Nefazodone hydrochloride exhibits poor solubility in water, being defined as "sparingly soluble" under USP criteria. It has a dissociation constant (pKa=6.4) within the range of physiological pH, which means the solubility of this basic drug decreases further as pH is increased during transit from the stomach to the small intestine and colon. Therefore, the rate of release from a nefazodone extended-release dosage form cannot be controlled readily by oral formulation systems that rely on release of drug by diffusion. Matrix tablet systems based on hydrophobic polymers or waxy materials show a significant reduction in drug release as the pH of the release medium (including physiological fluids in vivo) increases to and exceeds the pKa value of nefazodone HCl. Conventional hydrogel matrix systems also behave in a similar manner and would face additional problems associated with the low water solubility of nefazodone HCl. These types of systems work well with more water soluble drugs, where drug release mechanism is based on diffusion of drug (in vitro and in vivo) from the hydrated matrix and can be more readily controlled by adjustment of viscosity and amount of polymer used in the formulation. Single polymer hydrophilic matrix systems based on non-ionic materials such as polyethylene oxide, high viscosity hydroxypropylmethylcellulose or hydroxypropylcellulose usually rely on diffusional control of release for drugs with adequate solubility in the physiological range. These systems are not readily adaptable to drugs with the solubility characteristics of nefazodone. Barrier coated pellet systems (for subsequent encapsulation or inclusion in tablet formulations) also work best with relatively water soluble drugs and are not suitable for nefazodone hydrochloride without using adjuvants in the formulation that enhance solubility of nefazodone in water. Such adjuvants would significantly increase the bulk of the formulation leading to unacceptably large tablets or capsules given the amount of nefazodone HCl required per dose.
Osmotic pump systems may not be readily adaptable for nefazodone because of the changing solubility with pH which may, in part, alter the osmotic driving force for drug release associated with solubility of the drug. Also, the total daily doses of nefazodone (200 to 600 mg) used in controlling the disorders for which the drug is effective may not be easily contained in a conveniently sized dosage form because of the levels of additional excipients these type of systems normally require for their functioning.
Using specific combinations of ionic and non-ionic gelling polymers, we have prepared pH-modulated hydrophilic matrix tablet formulations. These types of formulations are sensitive to the pH of the external environment and adjust their release rate in response to pH changes. As a result, these dosage forms control the release of nefazodone in vitro and in vivo in a way which overcomes the problems of preparing an extended-release formulation of nefazodone, with its low water solubility and with marked pH-dependent solubility in the physiological pH range.
Drug Doses
Nefazodone daily doses fall within the range of 200 to 600 mg for the twice daily, immediate-release systems. It could be possible to contain all but the uppermost end of this range in a single unit dosage form, especially if that were a tablet formulation, for some types of controlled-release system. A dosage form containing 400 to 500 mg of drug might be expected to weigh less than 1000 mg. However, as has been pointed out above, reducing the rate of nefazodone release into the gastrointestinal tract from a controlled-release dosage form might be expected to increase the extent of drug metabolism. This would mean that for nefazodone, formulated into many existing controlled-release systems, the amount of drug administered, in order to provide for plasma levels similar to the immediate-release formulation, would have to be increased. Increased drug amounts would require higher payloads for any delivery system and unit size would increase to an unacceptable point. As a result, the total daily dose would have to be provided within two or more dosage units. Furthermore, having to change total daily dose in switching from immediate-release nefazodone to the controlled-release formulation is undesirable as this can be confusing to the patient and difficult for the prescribing physician. A delivery system that could minimize the increase in extent of metabolism and/or loss of bioavailability resulting from a controlled-release formulation is therefore highly desirable.
The extended-release nefazodone formulation of the present invention employs a novel pH-modulated release mechanism. It can be distinguished from prior release-extending mechanisms such as described in U.S. Pat. No. 4,792,452 to Howard, et al. which involve pH-independent release.
Nefazodone has been disclosed previously in connection with a sustained-release oral dosage form. WO 97/47285 discloses delivery systems intended to release drug at a controlled rate in the stomach or upper intestine exclusively. Retention in the stomach is promoted by inclusion of a chemical agent that induces the stomach to function in the fed (as opposed to fasted) mode. Several classes of agents are disclosed as providing this effect including serotonin receptor antagonists, of which nefazodone is listed as one of the members of this class. In effect, nefazodone is not the active drug whose release is being controlled, but instead is included as an ingredient for its postulated effect on the stomach.
In summary, nothing in the prior art suggests the novel pH-modulated nefazodone extended-release formulations of the present invention. Specifically, overcoming the inherent difficulties presented with the metabolism, solubility and magnitude of dose characteristics of nefazodone, as well as maintaining comparable bioavailability of parent drug while reducing undesirable metabolite levels, underscores the novelty and inventive step associated with these new formulations.